Vascular endothelial growth factor (VEGF) is a central regulator of angiogenesis (formation of new blood vessels from pre-existing vessels) and vasculogenesis (development of embryonic vasculature through an influence on endothelial cell differentiation and organization). Diseases that are characterized by abnormal angiogenesis and vasculogenesis, such as cancer, show abnormal production of VEGF. Thus, control of VEGF function may be one means to control or treat these diseases.
It is known that VEGF exists in multiple protein isoforms such as VEGF165, VEGF121, VEGF145, VEGF183, VEGF189, VEGF206. The isoforms arise from alternate splicing of the VEGF gene, and exhibit different heparin proteoglycan and extracellular matrix binding properties. VEGF165 is the predominant secreted isoform and has limited heparin-binding activity; VEGF121 is freely soluble and is devoid of heparin-binding activity.
It is also known that VEGF binds to receptor systems to exert its physiological and pharmacological effects. These receptors include the three different VEGF receptor kinases, termed vascular endothelial growth factor receptor-1 (VEGFR-1)/fms-like tyrosine kinase, vascular endothelial growth factor receptor-2 (VEGFR-2)/fetal liver kinase (flk-1)/KDR, vascular endothelial growth factor receptor-3 (VEGFR-3)/fms-like tyrosine kinase 4, as well as the non-kinase receptors Neuropilin-1 (NP-1) and Neuropilin-2 (NP-2). NP-1 and NP-2 receptors are known to bind VEGF165 and Placental Growth Factor-2 (PIGF-2), but do not bind either VEGF121 or the non-heparin binding Placental Growth Factor-1 (PIGF-1). NP-1 and NP-2 also bind various semaphorin ligands to mediate repulsive guidance activity in certain neuronal populations.
The ability of VEGF165 to bind to VEGFR-2 in the presence of NP-1 occurs through a VEGFR-2 co-receptor complex with NP-1 (VEGFR-2/NP-1). This is likely responsible for the increased potency of VEGF165 versus VEGF121 in endothelial cells co-expressing VEGFR-2 and NP-1, since the binding affinity of VEGF165 and VEGF121 is identical at VEGFR-2, and since VEGF165 has access to the complex, while VEGF121 has limited binding to the complex.
While the role of VEGFR-1 is unclear, the role of VEGFR-2 is well established as required for both vasculogenesis and angiogenesis. Hence, compounds that are capable of interacting with VEGFR-2 as receptor agonists have the potential to act as angiogenic agents, and would be useful for the treatment of diseases such as cardiac ischemia and peripheral vascular disease in which new blood vessel formation needs to be stimulated. Compounds that are capable of interacting with VEGFR-2 as receptor antagonists have the potential to act as anti-angiogenic agents, and would be useful for the treatment of diseases in which dysregulated angiogenesis is a characteristic pathology. Identification of such compounds, and methods of using these compounds, are thus desirable.